WO2005091697A2 - Thiourea compositions and uses thereof - Google Patents

Thiourea compositions and uses thereof Download PDF

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WO2005091697A2
WO2005091697A2 PCT/CN2005/000391 CN2005000391W WO2005091697A2 WO 2005091697 A2 WO2005091697 A2 WO 2005091697A2 CN 2005000391 W CN2005000391 W CN 2005000391W WO 2005091697 A2 WO2005091697 A2 WO 2005091697A2
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independently
aryl
occurrence
cycloalkyl
alkyl
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Dan Yang
Yingchun Chen
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The University Of Hong Kong
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
    • C07C1/321—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
    • C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • C07C2531/22—Organic complexes

Definitions

  • This invention relates to thiourea ligands and more particularly to thiourea-palladium complexes useful as catalysts for palladium catalyzed arylation of alkenes in a chemical reaction known as the Heck reaction, and as catalysts for palladium catalyzed Suzuki reactions of organoboric compounds and aryl halides.
  • the palladium catalyzed arylation of olefins is one of the most versatile tools for C-C bond formation in organic synthesis.
  • 111 Phosphine ligands are generally used to stabilize the reactive palladium intermediates, and excellent results have been reported for Pd-catalyzed Heck reactions when sterically bulky mono-phosphines, diphosphines, cyclometalated phosphines, or phosphites are used as the ligands. 12"51
  • the air- sensitivity of phosphine ligands places significant limits on their synthetic applications. Therefore, the development of phosphine-free palladium catalysts is a topic of enormous interest.
  • the invention provides thiourea-Pd(O) complexes that are air and moisture stable, highly active catalysts for the Heck reactions of aryl halides. More particularly, the invention provides the N,N'-disubstituted monothiourea ligand represented by generic structure I:
  • n is an integer in the range of 1 to 8 inclusive;
  • R 1 and R 2 are selected, independently for each occurrence, from the groups consisting of alkyl, cycloalkyl, aryl, aralkyl, and -(CH 2 ) m -R 80 ;
  • n is an integer in the range of 1 to 8 inclusive;
  • R 1 and R 2 are selected, independently for each occurrence, from the groups consisting of alkyl, cycloalkyl, aryl, aralkyl, and -(CH 2 ) m -R 80 ;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are selected, independently for each occurrence, from the groups consisting of H,
  • n is an integer in the range of 1 to 8 inclusive;
  • R 1 and R 2 are selected, independently for each occurrence, from the groups consisting of alkyl, cycloalkyl, aryl, aralkyl, and -(CH 2 ) m -R 80 ; R 3 , R 4 , R 5 , R 6 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 ,
  • Figure 1 shows some representative structures of thiourea ligands I.
  • Figure 2 shows some representative structures of thiourea ligands II.
  • Figure 3 shows some representative structures of thiourea ligands III.
  • Figure 4 shows structures of cis- and ra ⁇ s-PdCI 2 (1g) 2 . (Hydrogen atoms have been omitted for clarity. Thermal ellipsoids are shown at 30% probability).
  • the invention provides acyclic and cyclic thioureas 1a-q ( Figures 1 -3) and complexes thereof with Pd(0) or Pd(ll) ( Figure 4), which serve as catalysts for the Heck reaction between iodobenzene and methyl acrylate at
  • each thiourea ligand has a great influence on the catalytic efficacy of its palladium complex.
  • Acyclic thioureas 1a-c were almost completely inactive, as was also the case for the cyclic thiourea 1d featuring an NH moiety.
  • Good activity was observed, however, when using the ⁇ /,/V'-disubstituted bulky thioureas 1e-1q of different ring sizes as the ligands (Table 1 entries 1-8); the catalyst loading could be lowered down to 0.0001 mol%.
  • the reaction also could be conducted at high temperature under solvent-free conditions without affecting the catalytic
  • entry ligand Arl r ( Pd time yield (mol%) (h) 1 ig Phi ⁇ CO j Bu" 0.01 2 99 5 ig HaOOC ⁇ T ⁇ -Br COOMe 0.1 15 92 6 ig H 3 COC- ⁇ -Br Ph 0.1 15 99 7 ig PhBr Ph 0.1 24 74
  • Method A To a ⁇ /, ⁇ /-diaryl diamine solution in dry toluene was added 1 ,1'- thiocarbonyl diimidazole (1.2 equiv). Then the solution was stirred at 100°C and the reaction was monitored by TLC. After completion, the solution was diluted with ethyl acetate and washed with dilute HCI and brine. The organic layer was concentrated under vacuum. The pure thiourea was obtained through flash chromatography or recrystallization from 95% ethanol.
  • Method B To a stirred mixture of ⁇ /, ⁇ / -diaryl diamine and Na 2 C0 3 (1.5 equiv) in dry THF was added a solution of thiophosgene (1.2 equiv) in THF dropwise at room temperature. After stirring at room temperature overnight, water and ethyl acetate were added. The organic layer was washed with dilute HCI and brine, dried and concentrated. The pure thiourea was obtained through flash chromatography or recrystallization from 95% ethanol.
  • CDCI 3 ⁇ 190.0, 149.1 , 142.9, 141.3, 129.8, 127.4, 124.1 , 54.0, 52.5, 35.6, 34.0, 32.0, 31.1 , 25.2, 24.2; IR (cm "1 ): 2958, 2865, 1609, 1440, 1397, 1362, 1244, 1185, 1133, 1026; ESI LRMS: 690(M, 2), 359(100); El HRMS: calcd for C 42 H 66 N 4 S 2 690.4729, found 690.4717.
  • Aryliodide or bromide 0.5 mmol
  • arylboric acid 0.6 mmol
  • K 2 C0 3 1.0 mmol
  • bis-thiourea-Pd(dba) 2 1q complex in NMP 2.5 ⁇ 10 "3 M solution
  • NMP/H 2 O (0.75 ml/0.25 ml) were added to a flask under aerobic conditions.
  • the flask was sealed with rubber septa and heated at the desired temperature.
  • reaction mixture was diluted with ethyl acetate, washed with brine, and dried over Na 2 S0 4 .
  • the solvent was removed and the residue was purified by a flash chromatography on silica gel to give the product.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention provides N,N'-disubstituted monothiourea or bis­thiourea-Pd(0) complexes that are useful as catalysts for palladium-catalyzed Heck reaction of aryl iodides and bromides with olefins, and as catalysts for palladium catalyzed Suzuki reactions of organoboric compounds and aryl halides (Formula A).

Description

THIOUREA COMPOSITIONS AND USES THEREOF
This application claims priority of provisional application u.s. serial no. 60/556,570, filed March 26, 2004, the contents of which are being incorporated herein by reference.
FIELD OF THE INVENTION This invention relates to thiourea ligands and more particularly to thiourea-palladium complexes useful as catalysts for palladium catalyzed arylation of alkenes in a chemical reaction known as the Heck reaction, and as catalysts for palladium catalyzed Suzuki reactions of organoboric compounds and aryl halides.
BACKGROUND OF THE INVENTION
The palladium catalyzed arylation of olefins (the Heck reaction) is one of the most versatile tools for C-C bond formation in organic synthesis.111 Phosphine ligands are generally used to stabilize the reactive palladium intermediates, and excellent results have been reported for Pd-catalyzed Heck reactions when sterically bulky mono-phosphines, diphosphines, cyclometalated phosphines, or phosphites are used as the ligands.12"51 The air- sensitivity of phosphine ligands, however, places significant limits on their synthetic applications. Therefore, the development of phosphine-free palladium catalysts is a topic of enormous interest. [6"8] Thioureas are air and moisture stable solids and have recently been employed as ligands in Ru-, Rh-, or Pd-catalyzed reactions.19,101 Very recently, Z. Yang[11] and coworkers reported the Heck and Suzuki reactions of highly active arenediazonium salts catalyzed by a chiral thiourea -Pd complex.
SUMMARY OF THE INVENTION
The invention provides thiourea-Pd(O) complexes that are air and moisture stable, highly active catalysts for the Heck reactions of aryl halides. More particularly, the invention provides the N,N'-disubstituted monothiourea ligand represented by generic structure I:
Figure imgf000003_0001
wherein n is an integer in the range of 1 to 8 inclusive; R1 and R2 are selected, independently for each occurrence, from the groups consisting of alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80; R3, R4, R5, and R6 are selected, independently for each occurrence, from the groups consisting of H, alkyl, halogenated alkyl, cycloalkyl, aryl, aralkyl, -(CH2)m-R80, COQRiy (where R¥ = alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80), and CO_NRuRy (where Ru or R1 = H, alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80); R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and the ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
The bis-thiourea ligand represented by generic structure li:
Figure imgf000004_0001
wherein n is an integer in the range of 1 to 8 inclusive; R1 and R2 are selected, independently for each occurrence, from the groups consisting of alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80; R3, R4, R5, R6, R7, R8, R9, and R10 are selected, independently for each occurrence, from the groups consisting of H,
alkyl, halogenated alkyl, cycloalkyl, aryl, aralkyl, -(CH2)m-R80, C_OORϊ (where Ry = alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80), and C_0_NRuRϊ (where Ru or R = H, alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80); R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and the ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
The bis-thiourea ligand represented by generic structure III:
Figure imgf000004_0002
wherein n is an integer in the range of 1 to 8 inclusive; R1 and R2 are selected, independently for each occurrence, from the groups consisting of alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80; R3, R4, R5, R6, R3, R5, R6, R7, R8, R9,
R10, R^, R12, R13 are selected, independently for each occurrence, from the groups consisting of H, alkyl, halogenated alkyl, cycloalkyl, aryl, aralkyl, - (CH2)m-R80, COOR, (where Ry = alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m- R80), and CONRuR, (where Ru or Rj, = H, alkyl, cycloalkyl, aryl, aralkyl, and - (CH2)m-R80); R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and the ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows some representative structures of thiourea ligands I.
Figure 2 shows some representative structures of thiourea ligands II.
Figure 3 shows some representative structures of thiourea ligands III.
Figure 4 shows structures of cis- and raπs-PdCI2 (1g)2. (Hydrogen atoms have been omitted for clarity. Thermal ellipsoids are shown at 30% probability).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention provides acyclic and cyclic thioureas 1a-q (Figures 1 -3) and complexes thereof with Pd(0) or Pd(ll) (Figure 4), which serve as catalysts for the Heck reaction between iodobenzene and methyl acrylate at
100 °C (Table 1).
Table 1. Screening thiourea ligands for the Pd-catalyzed Heck reaction of iodobenzene with methyl acrylate3 Pd(dba) /ligand C02Mθ Arl • NEt3, DMF Ar- 100 °C Pd time entry ligand yield" TON (mol%) (h) 1 1e 0.1 1 >99 103 2 ig 0.01 2 >99 104 3 1 h 0.01 2 >99 104 4 1 i 0.01 1.5 >99 104 5 11 0.01 6 86 8.6x103 6 1n 0.01 4 95 9.5x103 7 1o 0.01 4 45 4.5x103 8 1 0.01 4 99 10" 9 iq 0.01 2 99 104 10 1i 0.0001 48 50 5x105 11° 1n 0.001 0.5 99 105 1 2 iq 0.0002 5 99 5x105 13d 1n 0.0001 12 99 106 " Reactions were conducted under aerobic conditions. b Yield was determined by 1H NMR spectroscopy using nitrobenzene as the internal standard. " At 150°C. d At 180°C under solvent- free condition
The reactions were conducted in air and that all the reagents were used directly as received. The structure of each thiourea ligand has a great influence on the catalytic efficacy of its palladium complex. Acyclic thioureas 1a-c were almost completely inactive, as was also the case for the cyclic thiourea 1d featuring an NH moiety. Good activity was observed, however, when using the Λ/,/V'-disubstituted bulky thioureas 1e-1q of different ring sizes as the ligands (Table 1 entries 1-8); the catalyst loading could be lowered down to 0.0001 mol%. The reaction also could be conducted at high temperature under solvent-free conditions without affecting the catalytic
efficacy (entries 12 and 13).
The catalytic efficacy of the thiourea 1g-Pd(0) and 1q-Pd(0) complex in the Heck reaction was studied further with a number of aryl halides and
olefins at 100-130°C. Table 2 indicates that high yields were obtained using
0.01 mol% Pd catalyst for olefins such as butyl acrylates (entries 1 -2), Olefins
that are α- or β-subsituted are also suitable substrates and give trisubstituted
olefins, [12] but higher catalyst loadings and reaction temperatures were required (entries 3-4). In general, higher catalyst loadings and temperatures were required to force the completion of the reactions of the aryl bromides compared to the case of aryl iodides (entries 5-8). 3-Bromopyridine was also efficiently coupled with styrene in 90% yield in the presence of 0.1 mol% of Pd (entry 9). The deactivated bromide could be coupled at higher temperature
(entry 10, 160°C).
Table 2. Heck reaction of aryl iodides and bromides with olefins3
Figure imgf000008_0001
entry ligand Arl r=( Pd time yield (mol%) (h) 1 ig Phi ^^COjBu" 0.01 2 99
Figure imgf000008_0002
5 ig HaOOC→T ϊ-Br COOMe 0.1 15 92 6 ig H3COC-^^-Br Ph 0.1 15 99 7 ig PhBr Ph 0.1 24 74
Figure imgf000009_0001
Beller[13] reported that the Heck reactions of aryl chlorides could be greatly improved when using Bu4NBr as an ionic liquid solvent.1141 In fact, this system is also suitable for the thiourea 1g-Pd(0)-catalyzed Heck reactions of deactivated bromides and activated chlorides, when the reaction temperature is elevated slightly. The results were summarized in Table 3. Excellent yields were achieved for deactivated bromides after their reaction for 24 h in the presence of 0.5 mol% of Pd (entries 1-3), but incomplete conversion occurred when using 0.2 mol% Pd catalyst (entry 4). Under the same conditions, activated aryl chlorides were coupled successfully with styrene within 24 h when using 1 mol% of the Pd catalyst (entries 5-7). n-Butyl acrylate displayed reactivity that was slightly lower than that of styrene, but good yields were also obtained (entries 8-10). Chorobenzene itself, however, was completely inert, even when we used a higher loading of the Pd catalyst (2 mol%) (entry 11 ).
Table 3. Heck reactions of deactivated bromides and activated chlorides with olefins Pd(dba)2/1g R ArX + = -^ NaOAc, TBAB A 135 °C
Pd time yield entry ArX R (mol%) (h) (%)b 1 H.CO-^^-Br Ph 0.5 24 99
Figure imgf000009_0002
6 H3COC-A -Cl Ph 0.5 30 67 7 α A α Ph 1 24 99 o2 8 H3C0C— ^ β COOnBu 2 24 77 9 P oc-^ — α COOnBu 1 24 80 10 COO Bu 1 24 90
Figure imgf000010_0001
11 cxa Ph 2 24 <5
The Pd-catalysed Suzuki cross-coupling reaction of aryl halides with aryl boric acids provides a general and efficient synthetic route to biaryl compounds and has found wide application in many areas of organic synthesis.1151 The operationally simple and air-stable catalytic system of thiourea-Pd catalyst inspired us to investigate its scope in Suzuki reaction. As revealed in Table 4 using 1q as the ligand, for p-iodoanisole, excellent isolated yield was obtained
at a loading of 0.01 mol% Pd at 100°C after 3h under aerobic conditions (Table
3, entry 1 ).
Encouraged by the result, we began to evaluate the coupling reaction of aryl bromides with aryl boric acids. For activated bromides, almost quantitative yields were achieved within 3h in the presence of 0.1 mol% Pd under the same conditions (entries 2-6 ). On the other hand, low yield was obtained when
deactivated p-bromoanisole was applied at 0.5 mol% Pd at 120°C (entry 7),
and similar results were gained when a bulky monodentate 1i was used (entry 8). However, the yield could be increased adding 20 mol% TBAB (entry 9). For 3,5-difluorophenylboric acid, better result could be obtained when the reaction was conducted in neat TBAB (entry 10). Acceptable yield was achieved for p- nitrochlorobenzene at 1 mol% Pd adding 20 mol% TBAB (entry 11 vs 12). Notably 1 -bromostyrene also displayed high reactivity to phenylboric acid in thiourea-Pd system (entry 13). Moreover, potassium aryl trifluoroborates[16J have been found to be more reactive than the corresponding organoboric acid,
and high yields were obtained at only 0.1 mol% Pd at 100°C (entries 14 and 15).
We also conducted the Suzuki reaction at further decreased catalyst loading (0.01 mol%), and quantitative yield was obtained for 3-nitro-bromobenzene at
120°C in 3h (entry 16).
Table 4. Suzuki coupling reaction catalyzed by 1q-Pd(dba)2 Pd(dba)2-1q ArX + Ar1B(OH)2 Ar-, Ar1 K2CC ι3, NMP, H20 Entr Pd T t Yield Ar1X Ar2B(OH)2 y (mol%) (°C) (h) (%) 1 Hl∞-ζββ-t PhB(OH)2 0.01 100 3 92 2 PhB(OH)2 0.1 100 3 92° 3 PhB(OH)2 0.1 100 3 90 4 °»N7=\ PhB(OH)2 0.1 100 3 99
Figure imgf000011_0001
6 °=N7=V_ v -Br 0.1 100 2 99 7 PhB(OH)2 0.5 120 10 33 8 C PhB(OH)2 0.5 120 10 27 9 d PhB(OH)2 0.5 120 12 67
Figure imgf000011_0002
11 f 0&—V —a PhB(OH)2 1 130 40 10 1 2 d,f OjΛ-β V-CI PhB(OH)2 1 130 24 49 13 PhB(OH)2 0.1 100 1 80
14 i Br PhBF3K 0.1 100 1 99 15 PhBF3K 0.1 100 1.5 87 16 l Br PhB(OH)2 0.01 120 3 99 In conclusion, the palladium complexes of cyclic and acyclic thiourea demonstrated high thermal stability and excellent catalytic activity in Heck and Suzuki coupling reactions under aerobic conditions. Remarkable TONs and TOFs were achieved in the coupling reactions (TONs up to 1 ,000,000, TOFs up to 200,000, for the reaction of Phi and n-butyl acrylate).
Example 1.
Synthesis of cyclic thioureas 1f-1k: glyoxal NaBH(OAc)3 Ar-NH2 Ar-N N-Ar »- C2H5OH/H20 CH2CI2, reflux 80-93% 60-90%
Figure imgf000012_0001
Method A -N -N // V H FΓΛ // 75% Y s H /) 1j
Method B 8g% '
Figure imgf000012_0002
Figure imgf000012_0003
Scheme 1
Two methods were used for the synthesis of cyclic thiourea ligands (Scheme 1 ). Method A: To a Λ/,Λ/-diaryl diamine solution in dry toluene was added 1 ,1'- thiocarbonyl diimidazole (1.2 equiv). Then the solution was stirred at 100°C and the reaction was monitored by TLC. After completion, the solution was diluted with ethyl acetate and washed with dilute HCI and brine. The organic layer was concentrated under vacuum. The pure thiourea was obtained through flash chromatography or recrystallization from 95% ethanol.
Method B: To a stirred mixture of Λ/,Λ/ -diaryl diamine and Na2C03 (1.5 equiv) in dry THF was added a solution of thiophosgene (1.2 equiv) in THF dropwise at room temperature. After stirring at room temperature overnight, water and ethyl acetate were added. The organic layer was washed with dilute HCI and brine, dried and concentrated. The pure thiourea was obtained through flash chromatography or recrystallization from 95% ethanol.
Preparation of 1f: Using method A; 75% yield. M.p. 167-168 °C; 1H NMR (300 MHz,
CDCy δ 7.42 (d, J = 9.0 Hz, 4H), 6.95 (d, J = 9.0 Hz, 4H), 4.08 (s, 4H), 3.81 (s, 6H); 13C NMR (75 MHz, CDCI3) δ 182.2, 158.1 , 138.8, 127.5, 114.2, 55.4,
49.8; IR (cm"1): 1511 , 1443, 1285; LRMS (El): 314 (M+, 100); HRMS (El): calcd for C17H18N202S (M+) 314.1089, found 314.1088.
Preparation of 1g: Using method B; 85% yield. M.p. 218-218.5 °C; 1H NMR (400 MHz,
CDCy δ 6.91 (s, 4H), 3.94 (s, 4H), 2.26 (s, 6H), 2.24 (s, 12H); 13C NMR (75 MHz, CDCy δ 181.1 , 138.2, 136.6, 134.5, 129.5, 47.6, 21.1 , 17.8; IR (cm"1): 1488, 1331 , 1271 ; LRMS (FAB): 339 (M++1 , 100); HRMS (FAB): calcd for C21H26N2S (M++1 ) 339.1894, found 339.1879.
Preparation of 1h: Using method B; 70% yield. M.p. 152-153 °C; 1H NMR (300 MHz, CDCy δ 7.32 (t, J = 6.6 Hz, 2H), 7.20 (d, J = 7.5 Hz, 4H), 4.02 (s, 4H), 2.80- 2.70 (m, 4H), 2.69-2.60 (m, 4H), 1.33 (t, J = 7.5 Hz, 12H); 13C NMR (75 MHz, CDCy δ 182.6, 142.5, 136.1 , 128.8, 126.5, 49.1 , 24.0, 14.4; IR (cm"1): 1484, 1285; LRMS (El): 366 (M+, 39), 337 (100); HRMS (El): calcd for C23H30N2S (M+) 366.2130, found 366.2120.
Preparation of 1i: Diimine: 92% yield. 1H NMR (300 MHz, CDCI3) δ 8.27 (s, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 6.86 (s, 2H), 1.43 (s, 18H), 1.34 (s, 18H); 13C NMR (75 MHz, CDCI3) δ 158.6, 150.1 , 150.0, 140.4, 126.0, 123.8, 116.0, 35.3, 34.4, 31.3, 30.5; IR (cm"1): 1609, 1492, 1265; LRMS (El): 432 (M+, 100); HRMS (El): calcd for C30H44N2 (M+) 432.3504, found 432.3504. Diamine: 90% yield. 1H NMR (300 MHz, CDCI3) δ 7.18 (d, J = 6.1 Hz, 2H), 6.80 (s, 2H), 6.75 (d, J = 6.1 Hz, 2H), 4.18 (br s, 2H, NH), 3.57 (s, 4H), 1.39 (s, 18H), 1.32 (s, 18H); 13C NMR (75 MHz, CDCI3) δ 149.9, 146.2, 131.2, 126.0, 114.6, 110.0, 45.0, 34.4, 33.8, 31.4, 30.2; IR (cm"1): 3688, 3601 , 1561 , 1265; LRMS (El): 436 (M+, 20), 219 (100); HRMS (El): calcd for C30H48N2 (M+) 436.3817, found 436.3817. Thiourea li was prepared using method B. A solution of Thiophosgene in dilute THF must be dropped very slowly. 1i was isolated as a white solid (75% yield) after flash chromatography on silica gel. M.p. 212-214 °C; 1H NMR (400 MHz, CDCy δ 7.45 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.02 (s, 2H), 4.06-4.03 (m, 2H), 3.93-3.91 (m, 2H), 1.50 (s, 18H), 1.30 (s, 18H); 13C NMR (100 MHz, CDCI3) δ 183.5, 150.4, 145.0, 140.8, 128.0, 127.8, 125.3, 53.4, 35.4, 34.3, 32.1 , 31.3; IR (cm"1): 1418, 1275; LRMS (FAB): 479 (M+ + H); FAB-HRMS: calcd for C31H46N2S (M+ + H) 479.3460, found 479.3460.
Preparation of 1j: Using method A, 75% yield. M.p. 173-174 °C; 1H NMR (300 MHz, CDCI3) δ 7.41-7.15 (m, 10H), 3.82-3.77 (m, 4H), 2.32-2.24 (m, 2H); 3C NMR
(75 MHz, CDCI3) δ 180.7, 147.4, 129.2, 127.4, 125.8, 51.4, 22.3; IR (cm"1):
1494, 1285; LRMS (El): 268 (M+, 73); EI-HRMS: calcd for C16H16N2S (M+)
268.1034, found 268.1015. Preparation of 1k: To a stirred suspension of racemic 2,2'-diamino-6,6'-dimethoxy- biphenyl2 (60mg, 0.25 mmol) and NaBH(OAc)3 (212 mg, 1 mmol) in dichloromethane (10 mL) was added a solution of benzaldehyde (0.06 ml, 0.58 mmol) in dichloromethane (2 mL) dropwise at room temperature. Then the mixture was stirred overnight. Flash chromatography on silica gel gave Λ/,Λ/-dibenzyl diamine as a white solid (94 mg, 90%). 1H NMR (300 MHz, CDCI3) δ 7.26-7.11 (m, 12H), 6.38 (d, J = 8.2 Hz, 2H), 6.32 (d, J = 7.7 Hz, 2H), 4.32 (s, 4H), 4.17 (br s 2H), 3.70 (s, 6H); 13C NMR (75 MHz, CDCI3) δ 158.1 , 147.3, 139.9, 129.6, 128.4, 126.7, 126.6, 107.2, 104.2, 100.6, 55.7, 47.5; IR (cm"1): 3432, 3086, 3051 , 2938, 1586, 496, 1472, 1422, 1282, 1131 ; LRMS (El): 424 (M+, 33), 333 (100); HRMS (El): calcd for C28H28N202S (M+) 424.2151 , found 424.2138. Thiourea 1k was prepared using method B, 85% yield. M.p. 179-180
°C; 1H NMR (400 MHz, CDCI3) δ 7.27 (t, J = 8.2 Hz, 2H), 7.04-7.00 (m, 6H), 6.88 (d, J = 8.2 Hz, 2H), 6.83-6.80 (m, 6H), 5.72 (d, J = 15.3 Hz, 2H), 4.81 (d, J = 15.3 Hz, 2H), 3.75 (s, 6H); 13C NMR (75 MHz, CDCI3) δ 199.6, 157.2, 147.7, 137.1 , 128.7, 127.9, 127.5, 126.7, 121.8, 113.9, 108.8, 56.8, 55.9; IR (cm"1): 3051 , 1592, 1579, 1464, 1420, 1245, 1190; LRMS (El): 466 (M+, 100), 375 (86); HRMS (El): calcd for C29H26N202S (M+) 466.1715, found 466.1718.
Example 2.
Synthesis of acyclic bis-thiourea ligands: glyxoal 9 \ NaBH(OAc); Thiophosgene
Ar— NH2 Ar— N N-Ar Ar— NH HN-Ar C2H5OH/H20 DCM, reflux Et3N, DCM
Figure imgf000016_0001
Scheme 2
A solution of /V,/V'-diaryl diamine (1.0 mmol) and NEt3 (3 equiv) in THF was dropped to a stirred solution of thiophosgene (3.0 equiv) in dry THF at 0
°C. After stirred at room temperature overnight, the organic layer was washed
with water, dried and concentrated. For the synthesis of acyclic bis-thiourea, the dichloride obtained above
and excess secondary amine were heated at 100 °C in a sealed pressure
tube for 24 hours. Then the solution was diluted with EtOAc and washed with dilute HCI and brine. The organic layer was dried and concentrated. Flash chromatography gave the pure bis-thiourea as a white solid.
11: White solid, 95 % yield; m.p 225-226 °C; 1H NMR (400 MHz, CDCI3) δ
7.37-7.34 (m, 2H), 7.21-7.18 (m, 2H), 7.18-7.00 (m, 2H), 4.87-4.79 (m, 2H), 4.15-4.11 (m, 2H), 3.54-3.35 (m, 8H), 1.44-1.19 (m, 48H); 13C NMR (100 MHz,
CDCI3) δ 190.0, 149.1 , 142.9, 141.3, 129.8, 127.4, 124.1 , 54.0, 52.5, 35.6, 34.0, 32.0, 31.1 , 25.2, 24.2; IR (cm"1): 2958, 2865, 1609, 1440, 1397, 1362, 1244, 1185, 1133, 1026; ESI LRMS: 690(M, 2), 359(100); El HRMS: calcd for C42H66N4S2690.4729, found 690.4717.
1m: White solid, 40 % yield for two steps; m.p 222-224 °C; 1H NMR (400 MHz,
CDCy δ 6.83 (s, 4H), 4.29 (s, 4H), 3.30-3.27 (m, 8H), 2.25 (s, 6H), 2.18 (s,
12H), 1.39-1.36 (m, 4H), 1.17-1.15 (m, 8H); 13C NMR (100 MHz, CDC!3) δ
188.3, 141.3, 136.1 , 134.3, 130.0, 51.9, 50.9, 25.2, 24.2, 20.7, 19.1 ; IR (cm"1): 2934, 2851 , 1609, 1473, 1422, 1369, 1245, 1185, 1159, 1131 , 1027; El LRMS: 550 (M, 34), 152 (100); El HRMS: calcd for C32H46N4S2550.3164, found 550.3158.
1n: White solid, 38 % yield for two steps; m.p 197-199 °C; 1H NMR (400 MHz,
CDCI3) δ 6.82 (s, 4H), 4.29 (s, 4H), 3.30 (q, J = 6.8 Hz, 8H), 2.24 (s, 6H), 2.21
(s, 12H), 0.73 (t, J = 6.8 Hz, 12H); 13C NMR (100 MHz, CDCI3) δ 189.9, 141.6,
136.4, 135.0, 51.3, 46.0, 20.8, 19.2, 11.7; IR (cm'1): 2963, 2929, 1651 , 1486, 1441 , 1411 , 1370, 1348, 1274, 1223, 1185, 1152, 1120, 1081 , 1013; El LRMS: 526 (M, 42), 277 (100); El HRMS: calcd for C30H46N4S2526.3164, found 526.3168.
Example 3
Synthesis of cyclic bis-thiourea ligand 1o:
Figure imgf000018_0001
1o
Preparation of 1o: To a stirred mixture of diamine salt (2.0g, 9.2mmol) and Na2C03 (0.85g, δmmol) in CH3CN (15 ml) was added slowly a solution of Bis(bromomethy)mesitylene (0.72g, 2.3mmol) in CH3CN (10 ml) at 81 °C. The resulting mixture was refluxed for 24h. Then the mixture was diluted with ethyl acetate and washed with brine, dried and concentrated. The resulting oil was dissolved in THF (30ml) and Na2C03 (1.27g, 12mmol) was added. Thiophosgene (0.7ml, 9mmol) in THF (10 ml) was dropped very slowly at room temperature. After stirred overnight, THF was removed, and water (20 ml) and ethyl acetate (40 ml) were added. The organic layer was washed with dilute HCI and brine, dried and concentrated. The pure bis-thiourea 1o was
obtained through flash chromatography (20% ethyl acetate/petroleum ether) as a white solid (150mg, 11 %).
1o: m.p >230 °C; 1H NMR (400 MHz, CDCI3) δ 6.97 (s, 1 H), 6.95 (s, 4H), 4.97
(s, 4H), 3.66 (t, J=8.4 Hz, 4H), 3.41 (t, J = 8.4 Hz, 4H), 2.43 (s, 3H), 2.40 (s,
6H), 2.29 (s, 6H), 2.22 (s, 12H); 13C NMR (100 MHz, CDCI3) δ 181.7, 138.6, 138.1 , 137.8, 136.5, 134.7, 130.8, 130.7, 129.4, 46.9, 46.3, 45.5, 21.0, 20.4, 17.7, 16.2; IR (cm"1): 2917, 1609, 1489, 1437, 1408, 1326, 1309, 1273, 1233, 1033; ESI LRMS: 585 (M+1 , 100); ESI HRMS: calcd for C35H44N4S2+Na 607.2905, found 607.2883.
Example 4
Synthesis of cyclic bis-thiourea ligands 1p and 1q:
Figure imgf000019_0001
1p: Ar=Mesιtyl 1q: Ar=2,5-Bul 2-Ph
Preparation of 1p and 1q: Borane-dimethylsulfide (2M in THF) (3.6ml 7.2mmol, δequiv.) was
added to a solution of diamide (0.9 mmol) in THF (20ml) at 0 °C. Then the
solution was refluxed overnight. After cooling to room temperature, methanol was added very slowly to destroy the excess borane. The solvent was removed. Methanol (10 ml) was added and removed again under reduced pressure. The resulting tetraamine was directly used in the next step. To a stirred mixture of tetraamine obtained above and Na2C03 (6 equiv.) in dry THF was added a dilute solution of thiophosgene in THF. Then the mixture was stirred at room temperature overnight. The pure cyclic bis- thiourea was obtained as a white solid through flash chromatography and
recrystalyzation from ethanol.
1p: White solid, 45% yield for two steps; m.p >230 °C; 1H NMR (400 MHz,
CDCI3) δ 8.20 (s, 1 H), 7.51-7.44 (m, 3H), 6.97 (s, 4H), 4.29 (t, J = 8.4Hz, 4H),
3.91 (t, J = 8.4 Hz, 4H), 2.31 (s, 6H), 2.28 (s, 12H); 13C NMR (100 MHz, CDCI3)
δ 180.7, 141.0, 138.3, 136.3, 134.7, 129.4, 128.6, 121.1 , 120.2, 49.3, 47.2, 21.0,
17.8; IR (cm"1): 2917, 1604, 1489, 1421 , 1306, 1277, 1076; ESI LRMS: 515 (M+1 , 100); ESI HRMS: calcd for C30H34N4O4S2+H 515.2303, found 515.2294.
1q: White solid, 41 % yield for two steps; m.p >230°C; 1HNMR (400 MHz,
CDCI3) δ 8.24-8.22 (m, 1 H), 7.53-7.43 (m, 3H), 7.38 (d, J = 2.0 Hz, 2H), 7.35
(d, J = 2.0 Hz, 2H), 7.11 (s, 2H), 4.29-4.18 (m, 4H), 4.13-4.07 (m, 2H), 4.01-
3.93 (m, 2H), 1.48 (s, 18H), 1.34 (s, 18H); 13C NMR (100MHz, CDCI3) δ 184.1 ,
150.5, 145.0, 141.2, 139.6, 128.8, 128.7, 128.2, 127.5, 125.5, 121.8, 121.6, 121.2, 52.6, 49.4, 35.4, 34.3, 31.9, 31.2; IR (cm"1): 2960, 1604, 1559, 1475, 1414, 1297, 1084; ESI LRMS: 655 (M+1 , 37), 639 (100); ESI HRMS: calcd for C40H54N4S2+H 655.3868, found 655.3864
Example 5
General procedure for Heck reaction of aryl iodides and olefins
Figure imgf000020_0001
Pd(dba)2 (1.5 mg, 0. 0025 mmol) and thiourea (4 equiv) were stirred in
DMF (0.5 mL) for 0.5 h at rt. Iodobenzene (0.28 mL, 2.5 mmol, substrate/catalyst ratio = 1000:1 ) and methyl acrylate (0.27 mL, 3.0 mmol) and TEA (0.42 mL, 3.0 mmol) were then added. The flask was sealed with rubber septa and heated at 100°C (the same result was obtained when the reaction was conducted with a condenser in open air). After the indicated time, the solution was diluted with ethyl acetate (20 mL) and washed with water and brine. Ethyl acetate was removed under vacuum and nitrobenzene (0.128 mL) was added as an internal standard. The yield of coupling product was determined by 1H NMR (400 MHz or 300 MHz) analysis, by comparing the peak intensities of the α/β-H of the product and the ortho- of nitrobenzene (internal standard). ^COOMe
PI 1H NMR (300 MHz, CDCI3) δ 7.67-7.63 (m, 2H), 7.54 (d, J = 4.1 Hz,
2H), 7.38 (d, J = 3.3 Hz, 1 H), 7.10 (t, J = 6.5 Hz, 1 H), 6.44 (d, J = 16.1 Hz, 1 H), 3.81 (s, 3H). To determine the reaction yield, the product peak at 6.44 ppm was selected for comparison with that of the ortho-H (at 8.20 ppm) of nitrobenzene (internal standard). COOBu-n prf 1H NMR (400 MHz, CDCI3) δ 7.73 (d, J = 16.0 Hz, 1 H), 7.52-7.57
(m, 2H), 7.40-7.45 (m, 3H), 6.49 (d, J = 16.0 Hz, 1 H), 4.26 (t, J = 6.9 Hz, 2H),
1.71-1.78 (m, 2H), 1.54-1.45 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H). ph^AooBu-t 1 H NMR (300 mz CDC|3) δ J 73 (d] j _ 1 6 0 HZ] 1 H) 7 53_7 57
(m, 2H), 7.40-7.45 (m, 3H), 6.49 (d, J = 16.0 Hz, 1 H), 1.34 (s, 9H). Ph
PΓT 1H NMR (300 MHz, CDCI3) δ 7.53 (d, J = 7.2 Hz, 4H), 7.38 (dd, J = 7.1 ,
1.5 Hz, 4H), 7.28 (d, J = 7.2 Hz, 2H), 7.13 (s, 2H). ^ .OCH3 ptf 1H NMR (300 MHz, CDCI3) δ 7.55 (d, J = 9.4 Hz, 2H), 7.52 (d, J =
16.0 Hz, 1 H), 7.40 (t, J = 3.5 Hz, 3H), 6.72 (d, J = 16.0 Hz, 1 H), 2.39 (s, 3H).
Figure imgf000021_0001
1H NMR (300 MHz, CDCI3) δ 7.63 (d, J = 16.2 Hz, 1 H), 7.43
(d, J = 6.2 Hz, 2H), 7.35 (d, J = 6.2 Hz, 2H), 6.40 (d, J = 16.2 Hz, 1 H), 4.26 (t, J = 6.9 Hz, 2H), 1.78 1.71 (m, 2H), 1.54 1.45 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H). /=, COOBu-n
H=co -f ^ 1H NMR (400 MHz, CDCI3) δ 7.68 (d, J = 16.0 Hz, 1 H), 7.51 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 6.36 (d, J = 16.0 Hz, 1 H), 4.25 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H), 1.76-1.70 (m, 2H), 1.52-1.46 (m, 2H),
1.02 (t, J = 7.5 Hz, 3H). ,COOBu-n
H2N- W 1H NMR (400 MHz, CDCI3) δ 7.70 (d, J = 8.4 Hz, 2H), 7.56
(d, J = 15.7 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 15.7 Hz, 1 H), 6.17 (s, 2H), 4.26 (t, J = 6.9 Hz, 2H), 1.78 1.77 (m, 2H), 1.54-1.45 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H). COOMe
PH - 1H NMR (300 MHz, CDCI3) δ 7.55 (d, J = 6.9 Hz, 2H), 7.40-7.19 (m, 4H), 3.82 (s, 3H), 2.13 (s, 3H). \ __ COOMe
Ph' 1H NMR (300 MHz, CDCI3) δ 7.53-7.45 (m, 3H), 7.37-7.35 (m, 2H),
6.13 (q, J = 1.2 Hz, 1 H), 3.75 (s, 3H), 2.58 (d, J = 1 .3 Hz, 3H).
Example 6
General procedure for Heck reaction of aryl bromides and olefins Pd(dba)2-1g R R ArBr + =/ NaOAc, NMP Ar' 130 °C Pd(dba)2 (1.5 mg, 0. 0025 mmol) and thiourea 1g (3.4 mg, 0.01 mmol) were stirred in NMP (0.5 mL) for 0.5 h at rt. Aryl bromide (2.5 mmol, S/C = 1000), olefin (3.8 mmol) and sodium acetate 330 mg (3.8 mmol) were added in turn. Then the flask was sealed with a septa and heated at 130°C. After indicated time, the solution was dilute with ethyl acetate (20 mL) and washed with water and brine. Ethyl acetate was removed under vacuum and nitrobenzene (0.128 mL) was added as internal standard. The yield of coupling product was determined by 1H NMR (400 MHz or 300 MHz) analysis, by comparing the peak intensities of the α/β-H of the product and the ortho-H of nitrobenzene (internal standard). ^COO e
OHC- \-J 1H NMR (300 MHz, CDCI3) δ 9.99 (s, 1 H), 7.87 (d, J = 8.1
Hz, 2H), 7.70-7.62 (m, 3H), 6.52 (d, J = 15.9 Hz, 1 H), 3.79 (s, 3H). ,COOMe
HsCO°- / 1H NMR (300 MHz, CDCI3) δ 7.80-7.75 (m, 3H), 7.42 (d,
J = 6.8 Hz, 2H), 6.34 (d, J = 16.1 Hz, 1 H), 3.63 (s, 3H), 2.42 (s, 3H). H3coc- _ ^ 1H NMR (400 MHz, CDCI3) δ 7.53-7.45 (m, 4H), 7.36-7.32 (m, 4H), 7.28-7.26 (m, 2H), 7.17 (d, J = 12.3 Hz, 1 H), 7.07 (d, J = 12.3 Hz, 1 H), 2.55 (s, 3H).
noc _f 1H NMR (300 MHz, CDCI3) δ 7.85-7.32 (m, 15H), 6.24 (d, J = 16.2 Hz, 1 H). N=\ ==Ah
K β 1H NMR (300 MHz, CDCI3) δ 8.70 (d, J = 1.3 Hz, 1 H), 8.45 (d, J = 3.5 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 1 H), 7.36-7.33 (m, 2H), 7.30-7.25 (m, 4H), 7.10 (d, J = 16.2 Hz, 1 H), 7.00 (d, J = 16.2 Hz, 1 H).
Example 7
General procedure for Heck reaction of deactivated aryl bromides and activated chlorides with olefins Pd(dba)2-1g R R ArX + =/ NaOAc, TBAB Ar' 135 °C Pd(dba)2 (1.5 mg, 0. 0025 mmol), thiourea 1g (3.4mg, 0.01 mmol) and sodium acetate (33 mg, 3.8 mmol) were stirred in molten TBAB (0.5 g) for 10 min at 100°C. Aryl halide (0.25 mmol, S/C=100) and olefin (0.38 mmol) were added in turn. Then the flask was sealed with a septa and heated at 135°C. After indicated time, the solution was dilute with ethyl acetate (20 mL) and washed with water and brine. Ethyl acetate was removed under vacuum and nitrobenzene (0.0128 mL) was added as internal standard. The yield of coupling product was determined by 1H NMR (400 MHz or 300 MHz) analysis, by comparing the peak intensities of the α/β-H of the product and the ortho-H of nitrobenzene (internal standard).
H3∞" ^^ 1H NMR (400 MHz, CDCI3) δ 7.64-7.52 (m, 4H), 7.45-7.40 (m, 3H), 7.33 (d, J = 12.1 Hz, 1 H), 7.10 (d, J = 12.1 Hz, 1 H), 6.98 (d, J = 8.2 Hz, 2H), 3.88 (s, 3H).
Figure imgf000023_0001
1H NMR (400 MHz, CDCI3) δ 7.93 (d, J = 7.0 Hz, 1 H), 7.74 (d, J = 7.0 Hz, 1 H), 7.60-7.51 (m, 5H), 7.39-7.30 (m, 3H), 7.07 (d, J = 16.1 Hz, 1 H). COOBu-n
^NO2 1H NMR (400 MHz, CDCI3) δ 8.13 (d, J = 17.3 Hz, 1 H), 8.05 (d, J
= 7.8 Hz, 1 H), 7.84 (d, J = 6.8 Hz, 1 H), 7.27-7.24 (m, 2H), 6.36 (d, J = 17.3 Hz, 1 H), 4.22 (t, J = 5.0 Hz, 2H), 1.71-1.67 (m, 2H), 1.32-1.28 (m, 2H), 0.96 (t, J = 6.8 Hz, 3H). /=. ^COOBU-n (H 3 C) 2 N /_^^ 1H NMR (300 MHz, CDCI3) δ 7.62 (d, J = 15.6 HZ, 1 H),
7.41 (d, J = 7.1 Hz, 2H), 6.66 (d, J = 7.1 Hz, 2H), 6.22 (d, J = 15.6 Hz, 1 H), 4.18 (t, J = 6.7 Hz, 2H), 3.00 (s, 6H), 1.71-1.66 (m, 2H), 1.47-1.40 (m, 2H), 0.96 (t, J = 8.2 Hz, 3H).
Example 8
General procedure for the Suzuki reaction of Aryl halides with boric acids Pd(dba)2/1q Ar1Br + Ar2B(OH)2 *" Ar1-Ar2 K2C03, NMP/H20
Aryliodide or bromide (0.5 mmol), arylboric acid (0.6 mmol), K2C03 (1.0 mmol), bis-thiourea-Pd(dba)2 1q complex in NMP (2.5χ10"3 M solution) and
NMP/H2O (0.75 ml/0.25 ml) were added to a flask under aerobic conditions.
The flask was sealed with rubber septa and heated at the desired temperature.
The reaction mixture was diluted with ethyl acetate, washed with brine, and dried over Na2S04. The solvent was removed and the residue was purified by a flash chromatography on silica gel to give the product.
Figure imgf000024_0001
1H NMR (200 MHz, CDCI3) δ 7.56-7.50 (m, 4H), 7.44-
7.37 (m, 2H), 7.32-7.25 (m, 1 H), 6.97 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H).
Figure imgf000025_0001
1H NMR (200 MHz, CDCI3) δ 10.05 (s, 1H), 7.97-7.93 (m,
2H), 7.77-7.72 (m, 2H), 7.66-7.61 (m, 2H), 7.52-7.39 (m, 3H).
^ — COOCH3 n ΗNMR (200 MHz, CDCI3) δ 8.10 (d, J = 8.2 Hz, 2H),
7.68-7.60 (m, 4H), 7.49-7.36 (m, 3H), 3.93 (s, 3H).
Figure imgf000025_0002
°2 1H NMR (200 MHz, CDCI3) δ 8.45 (m, 1H), 8.21-8.17 (m,
1H), 7.93-7.89 (m, 1H), 7.64-7.56 (m, 3H), 7.50-7.42 (m, 3H).
Figure imgf000025_0003
O, 1H NMR (400 MHz, CDCI3) δ 8.50-8.49 (m, 1H), 8.34 (d, J
= 8.0 Hz, 1 H), 8.06 (s, 2H), 7.98-7.95 (m, 2H), 7.73 (t, J = 8.0 Hz, 1 H).
Figure imgf000025_0004
1H NMR (200 MHz, CDCI3) δ 8.41-8.40 (m, 1H), 8.28-8.23
(m, 1H), 7.89-7.84 (m, 1H), 7.68-7.60 (m, 1H), 7.16-7.12 (m, 2H), 6.92-6.83 (m, 1H).
Figure imgf000026_0001
1HNMR (400MHz, CDCI3) δ 7.49 (d, J = 8.8 Hz, 2H),
7.09-7.03 (m, 2H), 6.98 (d, J - 8.8 Hz, 2H), 6.76-6.70 (m, 1 H), 3.86 (s, 3H).
Figure imgf000026_0002
1H NMR (200 MHz, CDCI3) δ 8.29 (d, J = 9.0 Hz, 2H),
7.73 (d, J = 9.0 Hz, 2H), 7.60 (m, 2H), 7.52-7.40 (m, 3H). '
Figure imgf000026_0003
(400MHz, CDCI3) δ 7.36-7.33 (m, 10H), 5.47 (s, 2H).
NOTES
The following notes correspond to the superscripts contained in the application. Each of the references listed below are incorporated by reference herein.
(1 ) (a) Heck, R. F. Ace. Chem. Res. 1979, 12, 146. (b) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. 1994, 33, 2379. (c) Cabri, W.; Candiani, I. Ace. Chem. Res. 1995, 28, 2. (d) Negishi, E.; Coperet, C; Ma, S.; Liou, S.; Liu, F. Chem. Rev. 1996, 96, 365. (e) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427. (f) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (g) Whitcombe, N. J.; Kuok Hii, K.; Gibson, S. E. Tetrahedron 2001, 57, 7449. (h) Dounay, A. B.; Overman, L. E. Chem Rev. 2003, 103, 2945 (2) (a) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10. (b) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (c) Shaughnessy, K. H.; Kim,
P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 2123. (d) Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 2677. (e) Ehrentraut, A.; Zapf, A.; Beller, M. Synlett 2000, 1589. (3) (a) Ben-David, Y.; Portnoy, M.; Gozin, M., Milstein, D. Organometallics 1992, 11, 1995. (b) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1655.
(c) Portnoy, M.; Ben-David, Y.; Milstein, D. Organometallics 1993, 12, 4734.
(d) Portnoy, M.; Ben-Dvid, Y.; Rousso, I.; Milstein, D. Organometallics 1994, 13, 3465. (e) Shaw, B. L; Perera, S. D. Chem. Commun. 1998, 1863. (4) For recent reviews on palladacycles for Heck reactions, see: (a) Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg. Chem. 2001, 1917. (b) Benford, R. B.
Chem. Commun. 2003, 1787. (5) For the use of tetraphenylphosphonium salts in Heck reactions, see: Reetz, M. T.; Lohmer, G.; Schwickardi, R. Angew. Chem., Int. Ed., 1998, 37, 481. (6) For phosphorus-free palladacycles as catalysts, see Ref. 4. (7) For recent reviews on Λ/-heterocyclic carbene-palladium catalysts, see: (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (b) Yong, B. S.; Nolan, S. P. Chemtracts-Organic Chemistry 2003, 205. (8) For recent reports on Heck reactions using catalysts that are air and moisture stable, see: (a) Buchmeiser, M. R.; Wurst, K. J. Am. Chem. Soc. 1999, 121, 11101. (b) Silberg, J.; Schareina, T.; Kempe, R.; Wurst, K.; Buchmeiser, M. R. J. Organomet. Chem. 2001, 622, 6. (c) Masllorens, J.; Moreno-Manas, M.; Pla-Quintana, A.; Roglans, A. Org. Lett. 2003, 5, 1559. (9) (a) Touchard, F.; Fache, F.; Lemaire, M. Tetrahedron: Asymmetry 1997, 8, 3319. (b) Touchard, F.; Gamez, P.; Fache, F.; Lemaire, M. Tetrahedron Lett. 1997, 38, 2275. (c) Touchard, F.; Bernard, M.; Fache, F.; Delbecq, F.; Guiral, V.; Sautet, P.; Lemaire, M. J. Organomet. Chem. 1998, 567, 133. (d) Tommasino, M. L.; Casalta, M.; Breuzard, J. A. J.; Lemaire, M. Tetrahedron: Asymmetry 2000, 11, 4835. (e) Breuzard, J. A. J.; Tommasino, M. L.; Touchard, F.; Lemaire, M.; Bonnet, M. C. J. Mol. Catal. A: Chem. 2000, 156, 223. (f) Touchard, F.; Bernard, M.; Fache, F.; Lemaire, M. J. Mol. Catal. A: Chem. 1999, 140, 1. (10) (a) De Munno, G.; Gabriele, B.; Salerno, G. Inorg. Chim. Ada 1995, 234, 181. (b) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. J. Organomet. Chem. 1995, 503, 21. (c) Zhang, T. Y.; Allen, M. J. Tetrahedron Lett. 1999, 40, 5813. (d) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297. (e) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765. (f) Hu, Y.; Yang, Z. Org. Lett. 2001, 3, 1387. (11) Dai, M.; Liang, B.; Wang, C; Chen, J.; Yang, Z. Org. Lett. 2004, 6, 221. (12) Gurtler, C; Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107 and references therein. (13) Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031. (14) For recent reviews on the use of ionic liquids as solvents, see: (a) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A: Chem. 2002, 182-183, 419.
(b) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667.
(c) Davis, J. H. Jr.; Fox, P. A. Chem. Commun. 2003, 1209. (15) For recent reviews on Suzuki coupling, see: (a) Hassan, J.; Sevignon, M.; Gozzi, C; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Miura, M. Angew. Chem. Int. Ed. 2004, 43, 2201. (16) (a) Darses, S.; Michaud, G.; Genet, J.-P. Eur. J. Org. Chem. 1999, 1875; (b) Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67, 8416. (b) Darses, S. Genet, J.-P. Eur. J. Org. Chem. 2003, 4313.

Claims

WE CLAIM:
1. The N,N'-disubstituted thiourea ligand represented by structure I:
Figure imgf000030_0001
wherein n is an integer in the range of 1 to 8 inclusive; RT and R2 are independently for each occurrence alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, and R6 are independently for each occurrence H, alkyl, halogenated alkyl, cycloalkyl, aryl, aralkyl, -(CH2)m-R80, CQOR., (where R^, =
alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80), and C_0_NRuR« (where Ru or R,,
= H, alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80); R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
2. The N,N'-disubstituted thiourea ligand of claim 1 , wherein: R., and R2 are independently for each occurrence 2,4,6-mesityl, 2,5-di-f- butylphenyl, 2,6-diethylphenyl or f-butyl; R3, R4, R5, and R6are absent; and n = 1 and 2.
3. The N,N'-disubstituted thiourea ligand represented by structure II:
Figure imgf000031_0001
wherein RT and R2 are independently for each occurrence alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; the A and A' rings of the biphenyl core independently are unsubstituted or substituted with R3 and R4, respectively, one, two, three, or four times; R3 and R4 are independently for each occurrence H, alkyl, cycloalkyl, aryl, aralkyl, halogen, alkoxyl, -SiR3, or -(CH2)m-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
4. The N,N'-disubstituted thiourea ligand of claim 3, wherein: R3 and R4 are absent, and R., and R2 are independently for each occurrence benzyl, 2,4,6-trimethylbenzyl, cyclohexyl or isopropyl.
5. The N,N'-disubstituted thiourea ligand of claim 3, wherein: R3 and R4 are methyl or methoxy, and R., and R2 are independently for each occurrence benzyl, 2,4,6-trimethylbenzyl, cyclohexyl or isopropyl.
6. The N,N'-disubstituted thiourea ligand represented by structure III:
Figure imgf000032_0001
wherein RT and R2 are independently for each occurrence alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; the four aryl rings of the binaphthyl core independently are unsubstituted or substituted with R3, R4, R5, and R6, respectively, any number of times up to the limitations imposed by stability and rules of valence; R3, R4, R5, and R6 are independently for each occurrence H, alkyl, cycloalkyl, aryl, aralkyl, halogen, alkoxyl, -SiR3, or -(CH2)m-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
7. The N,N'-disubstituted thiourea ligand of claim 6, wherein: R3, R4, R5, and R6 are absent; RT and R2 are preferentially selected, independently for each occurrence, from benzyl, 2,4,6-trimethylbenzyl, cyclohexyl and isopropyl.
8. The N,N'-disubstituted thiourea ligand represented by structure IV:
Figure imgf000033_0001
wherein n is an integer in the range of 1 to 8 inclusive; RT and R2are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, R6, R7, R8, R9, and R10 are, independently for each occurrence, H, alkyl, cycloalkyl, aryl, aralkyl, halogen, alkoxyl, -SiR3, or -
(CH2)m-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
9. The N,N'-disubstituted thiourea ligand of claim 8, wherein: RT and R2 are preferentially selected, independently for each occurrence, from 2,4,6-mesityl, 2,5-di-f-butylphenyl, 2,6-diethylphenyl or f-butyl; R3, R4, R5, and R6 are absent; R7=R8=R9= Rι0=ethyl, methyl, benzyl, C4H8, C5H10, or C6H12; and n = 1 and 2.
10. The N,N'-disubstituted thiourea ligand represented by structure V:
Figure imgf000034_0001
wherein n is an integer in the range of 1 to 8 inclusive; R3, R4, R5, R6, R7, R8, R9, R10, Rn, and R12 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; an aryl ring independently is unsubstituted or substituted with R13, any number of times up to the limitations imposed by stability and rules of valence; R13 is, independently for each occurrence, H, alkyl, cycloalkyl, aryl, aralkyl, halogen, alkoxyl, -SiR3, or -(CH2)m-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
11. The N,N'-disubstituted thiourea ligand of claim 10, wherein: RT and R2 are, independently for each occurrence, 2,4,6-mesityl, 2,5-di-f- butylphenyl, 2,6-diethylphenyl or f-butyl; R3, R4, R5, R6, R7, R8, R9, R10, RT T, and R12 are absent; R13 are 2,4, 6-trimethyl or 2, 4-dimethyl; and n = 1 and 2, m=1.
12. The N,N'-disubstituted thiourea ligand of claim 10, wherein: RT and R2 are, independently for each occurrence, 2,4,6-mesityl, 2,5-di-f- butylphenyl, 2,6-diethylphenyl or f-butyl; R3, R4, R5, R6, R7, R8, R9, Rτ0 are absent; R13 are absent; and n = 1 and 2, m=0.
13. The N,N'-disubstituted thiourea ligand represented by structure VI:
Figure imgf000035_0001
wherein n is an integer in the range of 1 to 8 inclusive; R3, R4, R5, R6, R7, R8, R9, and R10 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; aryl rings independently are unsubstituted or substituted with RTT and R12, any number of times up to the limitations imposed by stability and rules of valence;
RTT and R12 are, independently for each occurrence, H, alkyl, cycloalkyl, aryl, aralkyl, halogen, alkoxyl, -SiR3, or -(CH2)m-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
14. The N,N'-disubstituted thiourea ligand of claim 13, wherein:
RT and R2 are, independently for each occurrence, 2,4,6-mesityl, 2,5-di-f- butylphenyl, 2,6-diethylphenyl or f-butyl; R3, R4, Rg, R6, R7, Re, Rg, R10 are absent; RT T and R12 are absent; and n = 1 and 2.
15. The N,N'-disubstituted thiourea ligand represented by structure VII:
Figure imgf000036_0001
wherein n is an integer in the range of 1 to 8 inclusive;
R3, R4, R5, R6, R7, R8, R9, and R10 are, independently for each
occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; the four aryl rings of a binaphthyl core independently are unsubstituted
or substituted with RT , R12, R13, and R14, respectively, any number of times up
to the limitations imposed by stability and rules of valence;
RTT , R12, Ri3, and R14 are, independently for each occurrence, H, alkyl,
cycloalkyl, aryl, aralkyl, halogen, alkoxyl, -SiR3, or -(CH2)m-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl,
or another polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
16. The N,N'-disubstituted thiourea ligand of claim 15, wherein: RT and R2 are, independently for each occurrence, 2,4,6-mesityl, 2,5-di-f- butylphenyl, 2,6-diethylphenyl or -butyl; R3, R4, R5, R6, R7, R8, R9, Rτ0 are absent; RTT, R12, R13, and R14 are absent; and n = 1 and 2.
17. A method of producing aryl substituted olefins from aryl halides and olefins by a Heck reaction using a palladium catalyst and a N,N'-disubstituted thiourea ligand under conditions effective to generate aryl olefins (Scheme 1): Scheme 1
□ transition metal, Ar — X + =/ ligand of the present invention κ R X = l, Br, Cl base, >100 °C Ar
wherein Ar is an unsubstituted and substituted monocyclic aromatic moiety, or polycyclic aromatic or heteroaromatic moiety; X is Cl, Br, I, -OS(0)2alkyl, -OS(0)2aryl or -S02CI; R is H, alkyl, aryl, heteroaryl, aralkyl, alkyoxyl, amino, or trialkylsilyl; the transition metal is a Group VIIIA metals (Pd(dba)2, Pd(OAc)2, PdCI2 , PdCI2 (CH3CN)2, or NiCI2, Ni(COD)2); the base is a carbonate, an acetate, a fluoride, a trialkylamine, a phosphate, an alkoxide, or an amide; the N,N'-disubstituted thiourea ligand is one of structures 1-8 inclusive:
Figure imgf000038_0001
wherein n is an integer in the range of 1 to 8 inclusive; RT and R2are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, and R6 are, independently for each occurrence, H, alkyl, halogenated alkyl, cycloalkyl, aryl, aralkyl, -(CH2)m-R80, CQQR., (where βγ = alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80), or C_0_NRuRM (where Ru or F =
H, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80); R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000038_0002
wherein A and A' independently represent fused rings of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, or heterocyclic rings, the rings having 4 to 8 backbone atoms; RT and R2are, independently for each occurrence, alkyl, cycloalkyl, aryl,
aralkyl, or -(CH2)m-R80; R3, R4, R5, and R6, for each occurrence, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -
(CH2)-R80; R7 and R8, for each occurrence, independently represent halogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; A and A' independently are unsubstituted or substituted with R7 and R8, respectively, any number of times up to the limitations imposed by stability and the rules of valence; R3 and R5, or R4 and R6, or both, taken together optionally represent a ring having 5-7 atoms in the backbone of the ring; the ring having zero, one or two heteroatoms in its backbone; and being subsitituted or unsubstituted; R80 represents independently for each occurrence unsubstituted of substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000040_0001
wherein RT and R2 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, R6, R7, R8, R9, and R10, for each occurrence, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; R80 represents independently for each occurrence unsubstituted of substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000040_0002
wherein RT and R2 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, R6, R7, R8, R9, and R10, for each occurrence, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate. carbonvl cqrboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; the A and A' rings of the binaphthyl core independently are unsubstituted or substituted with R7 and R8, respectively, any number of times up to limitations imposed by stability and the rules of valence; R80 represents independently for each occurrence unsubstituted of substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000041_0001
wherein n is an integer in the range of 1 to 8 inclusive; RT and R2 are selected, independently for each occurrence, from the
groups consisting of alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80;
R3, R4, R5, R6, R7, R8, R9, R10 are, independently for each occurrence, H,
alkyl, halogenated alkyl, cycloalkyl, aryl, aralkyl, -(CH2)m-R80, COOR.. (where
R, = alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80), and CONRuR„ (where Ru
or R^, = H, alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80);
R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl,
or another polycycle;
. m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and
the N, N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
Figure imgf000042_0001
wherein n is an integer in the range of 1 to 8 inclusive; R3, R4, R5, R6, R7, R8, R9, R10, Rτι, and R12 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; Aryl ring independently is unsubstituted or substituted with R13, any number of times up to the limitations imposed by stability and rules of valence; R13 is, independently for each occurrence, hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000042_0002
wherein n is an integer in the range of 1 to 8 inclusive; R3, R4, R5, R6, R7, R8, R9, and R10 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; Aryl rings independently is unsubstituted or substituted with RTT and R12, any number of times up to the limitations imposed by stability and rules of valence; RT T and R12 are, independently for each occurrence, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive;
and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000043_0001
wherein n is an integer in the range of 1 to 8 inclusive; R3, R4, R5, R6, R7, R8, R9, and R10 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; the four aryl rings of the binaphthyl core independently are
unsubstituted or substituted with RTT, R12, RI3, and R14, respectively, any number of times up to the limitations imposed by stability and rules of valence; RTT, R12, R13, and R14 are selected, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
18. The method of claim 17, wherein the N,N'-disubstituted thiourea ligand is structure 1; the transition metal is palladium; and the base is trialkylamine, acetates, fluorides, carbonates, phosphate, hydroxides, and amides.
19. The method of claim 18, wherein RT and R2 are preferentially selected, independently for each occurrence, from 2,4,6-mesityl, 2,5-di-f-butylphenyl, 2,6-diethylphenyl and f-butyl; R3, R4, R5, and R6 are absent; and X represents I, Br, or Cl; R represents alkyl, aryl, heteroaryl.
20. The method of claim 17, wherein the N,N'-disubstituted thiourea ligand is structure 5, the transition metal is palladium; and the base is trialkylamine, acetates, fluorides, carbonates, phosphate, hydroxides, and amides.
21. The method of claim 20, wherein RT and R2 are preferentially selected, independently for each occurrence, from 2,4,6-mesityl, 2,5-di-f-butylphenyl, 2,6-diethylphenyl and f-butyl; R3, R4, R5, and R6are absent; R7=R8=R9= Rτ0=ethyl, methyl, benzyl, C4H8, C5H10, C6Hι2; n = 1 ; X represents I, Br, or Cl; R represents alkyl, aryl, heteroaryl.
22. The method of claim 17, wherein the N,N'-disubstituted thiourea ligand are structure 6; the transition metal is palladium; and the base is trialkylamine, acetates, fluorides, carbonates, phosphate, hydroxides, and amides.
23. The method of claim 22, wherein RT and R2 are preferentially selected, independently for each occurrence, from 2,4,6-mesityl, 2,5-di-f-butylphenyl, 2,6-diethylphenyl and f-butyl; R3, R4, R5, R6, R7, R8, R9, RTO are absent; Ri3 are absent; n = 1 , m=0; X represents I, Br, or Cl; R represents alkyl, aryl, heteroaryl.
24. The method of claim 23, wherein the yield of ArCH=CHR is between about 50 and about 99%.
25. The method depicted in Scheme 2: Scheme 2 transition metal, Ar__x + Ar'B(OH)2 ligand ofthe present invention Ar _Ar, base wherein Ar and Ar' are independently selected from the group consisting of unsubstituted or substituted monocyclic or polycyclic aromatic or heteroaromatic moieties; X is Cl, Br, I, -OS(0)2alkyl, -OS(0)2aryl, or -S02CI ; the transition metal is a Group VINA metal (Pd(dba)2, Pd(OAc)2, PdCI2 and NiCI2, Ni(COD)2); the base is a carbonate, an acetate, a trialkylamine, a phosphate, or an alkoxide; the N,N'-disubstituted thiourea ligand is one of structures 1-8 inclusive:
Figure imgf000046_0001
wherein n is an integer in the range of 1 to 8 inclusive; RT and R2 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, and R6 are, independently for each occurrence, H, alkyl, halogenated alkyl, cycloalkyl, aryl, aralkyl, -(CH2)m-R80, COOR.. (where R,, = alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80), or CONR^ (where Ru or Ra =
H, alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80); R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
wherein A and A' independently represent fused rings selected from the group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings having 4 to 8 backbone atoms; RT and R2 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, and R6, for each occurrence, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or - (CH2)-R80; R7 and R8, for each occurrence, independently represent halogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; A and A' independently are unsubstituted or substituted with R7 and R8, respectively, any number of times up to the limitations imposed by stability and the rules of valence; R3 and R5, or R4 and R6, or both, taken together optionally represent a ring having 5-7 atoms in the backbone of said ring; said ring having zero, one or two heteroatoms in its backbone; and said ring is subsitituted or
unsubstituted; R80 represents independently for each occurrence unsubstituted of substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000048_0001
wherein RT and R2are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, R6, R7, R8, R9, and R10, for each occurrence, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; R80 represents independently for each occurrence unsubstituted of substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000049_0001
wherein RT and R2 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; R3, R4, R5, R6, R7, R8, R9, and R10, for each occurrence, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; the A and A' rings of the binaphthyl core independently are unsubstituted or substituted with R7 and R8, respectively, any number of times up to limitations imposed by stability and the rules of valence; R80 represents independently for each occurrence unsubstituted of substituted aryl, cycloalkyl, cycloalkenyl, or polycyclyl; m is independently for each occurrence an integer in the range 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000049_0002
wherein n is an integer in the range of 1 to 8 inclusive; RT and R2are, independently for each occurrence, alkyl, cycloalkyl, aryl,
aralkyl, or -(CH2)m-R80; R3, R4, R5, R6, R7, R8, R9, R10are, independently for each occurrence, H, alkyl, halogenated alkyl, cycloalkyl, aryl, aralkyl, -(CH2)m-R80, COOR;. (where
Rv = alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80), or C_ONRuRy (where Ru or
R = H, alkyl, cycloalkyl, aryl, aralkyl, and -(CH2)m-R80); R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and
the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000050_0001
wherein n is an integer in the range of 1 to 8 inclusive;
R3, R4, R5, R6, R7, R8, R9, R10, Rn, and R12 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; the aryl ring independently is unsubstituted or substituted with R13, any number of times up to the limitations imposed by stability and rules of valence; R13 is selected, independently for each occurrence, for each occurrence, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to 8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer;
Figure imgf000051_0001
wherein n is an integer in the range of 1 to 8 inclusive; R3, R4, R5, R6, R7, R8, R9, and R10 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; aryl rings independently are unsubstituted or substituted with RTT and
R12, any number of times up to the limitations imposed by stability and rules of valence; RTT and R12, independently for each occurrence, represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer; or
Figure imgf000052_0001
wherein n is an integer in the range of 1 to 8 inclusive; R3, R4, R5, R6, R7, R8, R9, and R10 are, independently for each occurrence, alkyl, cycloalkyl, aryl, aralkyl, or -(CH2)m-R80; the four aryl rings of the binaphthyl core independently are unsubstituted or substituted with RTT, R12, RI3, and R14, respectively, any number of times up to the limitations imposed by stability and rules of valence; RTT, R12, R13, and R14 are, independently represent hydrogen, alkyl, alkenkyl, alkynyl, alkoxyl, silyloxy, nitro, alkylthio, amide, phosphoryl, phosphonate, carbonyl, carboxyl, carboxamide, silyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, guanidine, amidine, acetal, ketal, amine oxide, aryl, azide, carbamate, imide, oxime, sulfonamide, urea, or -(CH2)-R80; R80 represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, or another polycycle; m is independently for each occurrence an integer in the range of 0 to
8 inclusive; and the N,N'-disubstituted thiourea ligand, when chiral, is a mixture of enantiomers or a single enantiomer.
26. The method of claim 25, wherein the N,N'-disubstituted thiourea ligand is structure 1; the transition metal is palladium; and the base is trialkylamine, acetates, carbonates or phosphate.
27. The method of claim 26, wherein RT and R2 are, independently for each occurrence, 2,4,6-mesityl, 2,5-di- - butylphenyl, 2,6-diethylphenyl or f-butyl; R3, R4, R5, and R6 are absent; X represents I, Br, or S02CI; and Ar and Ar' represent aryl, or heteroaryl.
28. The method of claim 25, wherein the N,N'-disubstituted thiourea ligand is structure 5; the transition metal is palladium; and the base is a trialkylamine, an acetate, a fluoride, a carbonate, a phosphate, a hydroxide, or an amide.
29. The method of claim 28, wherein RT and R2 are, independently for each occurrence, 2,4,6-mesityl, 2,5-di- - butylphenyl, 2,6-diethylphenyl or f-butyl; R3, R4, R5, and R6are absent; R7=R8=R9= R10=ethyl, methyl, benzyl, C4H8, C5Hτ0, C6Hτ2; n = 1 ; and X represents I, Br, or S02CI; Ar and Ar' represent aryl or heteroaryl.
30. The method of claim 25, wherein the N,N'-disubstituted thiourea ligand is structure 6; the transition metal is palladium; and the base is a trialkylamine, an acetate, a fluoride, a carbonate, a phosphate, a hydroxide, or an amide.
31. The method of claim 30, wherein RT and R2 are preferentially selected, independently for each occurrence, from 2,4,6-mesityl, 2,5-di-f-butylphenyl, 2,6-diethylphenyl and t- butyl; R3, R4, R5, R6, R7, R8, R9, Rτ0 are absent; R13 is absent; n = 1 , m=0; X represents I, Br, or S02CI; and Ar and Ar' represent aryl or heteroaryl.
32. The method of claim 31 , wherein the yield of Ar-Ar' is between about 50% and about 99%.
PCT/CN2005/000391 2004-03-26 2005-03-28 Thiourea compositions and uses thereof WO2005091697A2 (en)

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